Project Summary/Abstract Molecular mechanisms underlying blood development and disorders are of great interest and importance from the perspective of understanding normal function and leukemias. Drosophila has long served as a genetic model for many developmental processes, but its usefulness as a hematopoietic model has only recently been appreciated. The mechanisms that maintain blood stem cells in Drosophila show remarkable conservation in strategy of development and function with mammalian systems. This study utilizes powerful genetic tools and reagents available for the Drosophila model system to understand how local and global signals affect blood cell development. In particular, we will analyze blood cell differentiation within the fruit fly blood-producing organ to assess how cell cycle, cell differentiation, and organ morphology are influenced during normal development as well as in the presence of stressful environmental stimuli. This proposal consists of three major aims. Aim 1 describes experiments aimed at mapping the organismal connection between defects in CO2 reception and blood cell maturation. In Aim 2 we propose to fully characterize the cell cycle profile of blood progenitors and we will uncover the signaling pathways regulating proteins controlling cell cycle progression. Finally, in Aim 3, we will identify and characterize the effects of tumor growth in epithelial tissue on blood cell development in the mesoderm derived hematopoietic organ. The role of tumor burden on the blood/immune system is of great importance to human cancer and injury, and Drosophila provides an ideal model for understanding the mechanisms in detail. Overall, the research we propose will lead to critical insights into how blood cells are influenced by external and internal stimuli, the mechanisms of which are likely to be conserved in humans.